The distribution of fitness effects (DFE) of new mutations across different environments quantifies the potential for adaptation in a given environment and its cost in others. So far, results regarding the cost of adaptation across environments have been mixed, and most studies have sampled random mutations across different genes. Here, we quantify systematically how costs of adaptation vary along a large stretch of protein sequence by studying the DFEs of the same ≈2300 amino-acid changing mutations obtained from deep mutational scanning of 119 amino acids in the middle domain of the heat-shock protein Hsp90 in five environments. This region is known to be important for client binding, stabilization of the Hsp90 dimer, stabilization of the N-terminal-Middle and Middle-C-terminal interdomains, and regulation of ATPase-chaperone activity. Interestingly, we find that fitness correlates well across diverse stressful environments, with the exception of one environment, diamide. Consistent with this result, we find little cost of adaptation; on average only one in seven beneficial mutations is deleterious in another environment. We identify a hotspot of beneficial mutations in a region of the protein that is located within an allosteric center. The identified protein regions that are enriched in beneficial, deleterious, and costly mutations coincide with residues that are involved in the stabilization of Hsp90 interdomains and stabilization of client binding interfaces, or residues that are involved in ATPase chaperone activity of Hsp90. Thus, our study yields information regarding the role and adaptive potential of a protein sequence that complements and extends known structural information.

中文翻译：

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酵母Hsp90中间结构域的适应潜力。

新突变的适应性效应（DFE）在不同环境中的分布量化了在给定环境中适应的潜力以及在其他环境中的适应成本。到目前为止，关于跨环境适应成本的结果好坏参半，并且大多数研究都对不同基因之间的随机突变进行了采样。在这里，我们通过研究热休克蛋白中间结构域中119个氨基酸的深度突变扫描获得的相同≈2300个氨基酸变化的突变的DFE，系统地量化了适应成本在整个蛋白序列中的变化方式Hsp90在五个环境中。已知此区域对于客户结合，Hsp90二聚体的稳定，N末端-中间和中间C末端域之间的稳定以及ATPase-伴侣活性的调节很重要。有趣的是，我们发现适应度在不同的压力环境中具有很好的相关性，只有一种环境，即二酰胺。与这个结果一致，我们发现适应成本很小；平均而言，七分之一的有益突变在另一种环境中是有害的。我们在变构中心内的蛋白质区域中确定了有益突变的热点。鉴定出的富含有益，有害和昂贵突变的蛋白质区域与参与Hsp90域间稳定化和客户结合界面稳定化的残基或参与Hsp90 ATPase伴侣活性的残基重合。从而，